The repair or augmentation of soft tissue defects or contour abnormalities caused by facial defects, acne, surgical scarring or aging has proven to be very difficult. A number of materials have been used to correct soft tissue defects with varying degrees of success, but currently no material appears to be completely safe and effective. In the past, small amounts of liquid silicone were used to correct minor soft tissue defects where minimal mechanical stress was present at the recipient site. Unfortunately, liquid silicone from these injections appears to migrate to distant body parts and can cause a variety of physiological and clinical problems. In response to these problems and the misuse of liquid silicone, the FDA has prohibited the use of liquid silicone in humans.
In the 1970's, reconstituted injectable bovine collagen became available as a potential treatment for soft tissue defects. However, over time, the benefits of collagen treatment have proven to be short-lived as the collagen reabsorbs in two to three months. Additionally, safety measures must be employed with this material to avoid allergic reactions to the bovine proteins in the collagen. In an attempt to solve these shortcomings, crosslinked collagen was introduced to extend effective treatment times to approximately six months. However, allergic reactions still occur with the crosslinked collagen material and frequent readministration of the crosslinked material is still required for efficacy.
Recently, several groups have investigated other materials that may be used for soft tissue repair or augmentation such as biocompatible ceramic particles in aqueous gels, thermoplastic materials, thermosetting materials and lactic acid based polymer blends, to overcome some of the problems previously experienced with collagen and liquid silicone.
Injectable implants containing biocompatible ceramic particles in an aqueous gel are described in U.S. Pat. No. 5,204,382 to Wallace et al. The implants consist of ceramic particles of calcium phosphate from a nonbiological source, mixed with an aqueous gel carrier in a viscous polymer (such as polyethylene glycol, hyaluronic acid, poly(hydroxyethyl methacrylate) and collagen). Although these materials are generally nontoxic, there appears to be risks associated with the use of nonabsorbable particulate materials related to the migration of these particles to distance sites in the body.
Injectable polymeric systems have also been reported. For example, hydrophilic solutions of a polymer in water or N-methylpyrrolidone (NMP) which form an implant as a result of diffusion of the solvent or water from the polymer solution have been investigated. However, the diffusion of the solvent or water reduces the size of the injected polymer, resulting in a composition which is not suitable as a filler for skin repair or augmentation (Y. J. Kim, Pharm. Res., 18(4) 548-550 (2001)).
Thermoplastic and thermosetting defect fillers are described in U.S. Pat. Nos. 4,938,763, 5,278,201 and 5,278,202 to Dunn et al. Dunn describes the use of both a thermoplastic material with a solvent and a thermosetting material with a curing agent to form solid implants in situ. Although the biodegradable materials proposed for use as thermoplastics appear to be biocompatible, the solvents necessary to dissolve them for injection into tissue may not be biocompatible. Additionally, the thermoplastic and thermosetting materials have limited utility in filling soft tissue because they solidify. Similar commercially available materials exhibit ultimate yield stresses of approximately 10,000 psi; in comparison, human skin exhibits ultimate yield stresses of from 500 to 2,000 psi. Therefore, due to palpability concerns, the thermoplastic and thermosetting materials described appear to be too hard for use in soft tissue augmentation or repair and especially in dermal augmentation or repair.
Soft tissue repair or augmentation has also been proposed using lactic acid-based polymer blends of amorphous oligomers with crystalline oligomers or polymers (see U.S. Pat. No. 4,235,312 to Buchholz et al.). These blends were developed to provide a pasty or waxy material which could be used as an absorbable implant to replace the brittle copolymers of lactic acid and glycolic acid already known for use as bone waxes. However, these blends do not appear to be suitable for use as injectable soft tissue defect fillers, because they are too viscous to be injected through a needle which significantly limits the utility of these blends. Furthermore, the low molecular weight liquid oligomers described in the '312 patent are slightly soluble in body fluids, which means that these oligomers will quickly diffuse out of the site of implantation to other areas of the body.
In view of the deficiencies of the soft tissue augmentation materials previously considered, there exists a need for soft tissue augmentation materials with improved mechanical properties. Ideally, any augmentation material would have several important characteristics not possessed by the prior art materials. For example, any soft tissue augmentation material should be completely biodegradable to avoid the possibility of long-term chronic irritation of tissues or migration of nonabsorbable materials over time to different areas of the body. The soft-tissue augmentation materials should also provide soft tissue augmentation for at least six months to avoid frequent readministration of the augmentation material. Furthermore, soft tissue augmentation materials should be of very low viscosity or particle size to allow easy administration by injection using a thin gauge needle (e.g., 27-30 G). Finally, the ideal soft tissue augmentation material would have the appropriate degree of pliability and viscosity for the tissue into which the new material was being implanted to provide life-like tissue augmentation or repair. As discussed above, none of the currently available materials have all of these characteristics.
Therefore, it is an object of the invention to provide injectable biocompatible, biodegradable polymer compositions suitable for soft tissue augmentation and/or repair, and methods of making and using thereof.